April, 1940
N 1 , N 4 - N ~ c o ~ mDERIVATIVES m OF SULFANILAMIDE [CONTRIBUTION FROM
THE
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COLLEGEOF PEARMACY OF THE UNIVERSITY OF CALIFORNIA]
N1,N4-Nicotinyl Derivatives of Sulfanilamide BY T. C. DANIELSAND HARRYIWAMOTO A comparatively large number of N1 and N 4 acyl derivatives' of sulfanilamide have been described and several have been reported to be of pharmacologic interest in the treatment of bacterial i n f e c t i o n ~ . ~ nThe ~ * ~ pharmacologic properties of nicotinic acid and of sulfanilamide suggested the desirability of preparing the nicotinyl derivatives. One of us in 1937 prepared the N4nico tinylsulfanilamide. Crossley, Northey and Hultquist3 have described the N1-nicotinylsulfanilamide and reported a melting point of 256257.5'. Our N 4 product had the same melting point and we therefore became interested in ascertaining whether rearrangement had occurred or the melting point of the two derivatives was a coincidence. Partial rearrangement of certain of the N*-acylsulfanilamides had been observed by Crossley, Northey and Hultquist.a We have prepared the N4-nicotinyl derivative by two general methods: (1) by the action of nicotinyl chloride5 on sulfanilamide in anhydrous pyridine, and (2) b y treating the anilide of nicotinic acid with chlorosulfonic acid followed by ammonia. The products obtained by the above methods give the same melting point and mixed melting point (257-258'). They do not titrate to a phenolphthalein end-point. We prepared the N l-nicotinylsulfanilamide from N4-acetylsulfanilamide b y the method of Crossley, Northey and Hultquist. This product melts a t the same temperature as the N4-nicotinyl derivative (257-258') but because of its greater acidity titrates quantitatively to a phenolphthalein end-point. A 50% mixture with the N4nicotinyl derivative melts a t 233-235'. The N1derivative after melting can still be titrated quantitatively with sodium hydroxide to a phenolphthalein end-point, which shows that rearrangement does not occur during the melting. All of the N4-acyl derivatives of sulfanilamide thus far described, with the exception of the nicotinyl, have a considerably higher melting point than the corresponding N1 compound^.^*^
The compounds studied crystallized in general as fine needles. Table I gives the analyses and melting points. TABLEI N1 acyl group
N' acyl group
Theoretical Assay, ,%, Meltin8 mol. wt. NaOH Nitrite points, C.
.
Nicotinyl 319.3 99.8 . 255-256 Acetyl" 319.3 99.8 . . 293-294 Nicotinylb 383.4 98.4 . . 222-248 ... . . . 277.3 100.5 . . 257-258 . . . . . . . Nicotinyl 277.3 . .. 99.9 257-258 " Prepared by the method of Crossley, Northey and HultquisLa * Product exists in two forms, one of which melts sharply a t 222, the other a t 248". Acetyl Nicotinyl Nicotinyl Nicotinyl"
Pharmacology.-Although the work of Fourneau, et a1.,6 indicated that the introduction of acyl groups on the N 4 nitrogen of sulfanilamide greatly reduces the antistreptoccic activity, compounds of this class have since been described which have equal or greater e f f e c t i v e n e s ~ . The ~~~ N4-nicotinylsulfanilamide has been studied by Leake, Karr, Finnegan and Murayama.' The preliminary work has indicated an effectiveness greater than that of sulfanilamide in the treatment of experimental hemolytic streptococcal infections and equal to sulfapyridine in experimental pneumococcal infections. The toxicity is much less than that of sulfanilamide or of sulfapyridine. Studies are now in progress on the N 1,N4-dinicotinylsulfanilamide and on the N1acetyl-N4-nicotinylsulfanilamide. The details of the pharmacologic investigation will be published elsewhere. Experimental Part
N4-Nicotiinylsulfanilamide.-(1) T o 14.2 g. (0.1 mole) of nicotinyl chloride and 17.2 g. (0.1 mole) of sulfanilamide was added 18.0 g. of anhydrous pyridine. The mixture was refluxed on a water-bath for one hour, cooled and several volumes of cold water added. The precipitate was collected on a filter and washed thoroughly with water followed by recrystallization from 50% alcohol; yield 50 to 75%. (2) To 58.3 g. (0.5 mole) of chlorosulfonic acid in a threenecked flask, equipped with a mechanical stirrer and reflux condenser cooled to O D , was added 9.9 g. (0.05 mole) of nicotinylanilide in divided portions with continuous agi(1) For nomenclature, see Crossley, Northey and Hultquist, THIS tation. The temperature during the addition was kept JOURNAL, 60, 2217 (1938). (2) Miller, Rock and Moore, ibid., 61, 1198 (1939). below 15", then gradually raised to 60" on a water-bath (3) Crossley, Northey and Hultquist, ibid., 61,2950 (1939). (4) Stuart, U. S. Patent 2,117,260; C. A , , 39, 5160 (1938). (5) Ingersoll and Robbins, THISJOURNAL, 48, 2451 (1926).
(6) Fourneau, cf al., Compt. vend. SOC. bioi., 111, 258 (1936). ( 7 ) Ledke, Karr and Murayama, unpublished report.
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J. E. ZANETTI AND J. T. BASHOUR
and maintained a t this temperature for two hours. The reaction mixture was cooled and treated directly with an excess of cold 28% ammonia solution, adding the ammonia in divided portions with continuous stirring. The stirring was continued for approximately one hour and the precipitate collected and washed several times with water followed by recrystallization from 50% alcohol; yield 40 to 50%. The melting point was identical with that of the product from (1) and gave the same mixed melting point. N1-Acetyl-N4-nicotinylsulfanilamide.-To 25 cc. of acetic anhydride was added gradually 2.8 g. (0.01 mole) of N4-nicotinylsulfanilamide. The mixture was refluxed for one hour and cooled in an ice-bath. The precipitate was collected and washed with water, then dissolved in sodium hydroxide (pH S ) , decolorized with activated charcoal and precipitated by the addition of dilute hydrochloric acid to p H of 5. The precipitate was filtered, washed and dried; yield approximately 50%. N1,N4-Dinicotinylsulfanilamide.-To 5.5 g. (0.02 mole) of N4-nicotinylsulfanilamide and 5.7 g. (0.04 mole) of nicotinyl chloride was added 20 cc. of anhydrous pyridine and the product refluxed for one hour. Several volumes of wa&r were added to the cooled reaction product and the solution acidified with dilute hydrochloric acid to a PH
Vol. 62
of 5. The precipitate was collected and washed with several portions of water, redissolved with sodium hydroxide to a ~ J H of 8, filtered and reprecipitated by the addition of dilute hydrochloric acid t o a PH of 5. The product was again washed and dried; yield approximately 40%. The product melts sharply at 222', resolidifies on heating and melts again a t 248". Titration with sodium hydroxide of the form melting a t 248' gives the same equivalent weight as before melting.
Summary 1. The N4-nicotinylsulfanilamide and N1,N4dinicotinylsulfanilamide are described. 2 . The melting points of N1 and N4-nicotinylsulfanilamide are the same. 3. The preliminary pharmacologic investigation indicates that the N4-nicotinylsulfanilamide is effective in the treatment of experimental hemolytic streptococcus infections and also certain types of pneumococcus infections. The toxicity of the N4-nicotinylsulfanilamide is lower than either sulfanilamide or sulfapyridine. SANFRANCISCO, CALIF.
RECEIVED JANUARY 2, 1940
[CONTRIBUTION FROM THE CHEMICAL LABORATORIES OF COLUMBIA UNIVERSITY ]
a-Furfurylpropylamhe and Di-a-furfuryl Tertiary Amines BY J. E. ZANETTIAND J. T. BASHOUR a-Furfurylpropylamine has now been synthesized by the same general method as previously used with other secondary a-furfuryl amines.' It is a colorless oil with a faint fishy odor boiling a t 8 0 - 8 1 O under 20 mm. pressure, d25~60.947, n% 1.4679. Its hydrochloride melts a t 138-140'. AnaE. Calcd. for CgH180N: N, 10.1. Fourid: N, 10.2. Very little has been done in the field of tertiary a-furfuryl amines and only one tertiary amine containing two furfuryl groups has been reported, namely, the tri-a-furfurylamine synthesized by Zanetti and Beckmann.z Von Braun and Kohler3 synthesized several tertiary furfurylamines which, however, contained only one a-furfuryl group and Von Braun and Braunsdorf* made an analog of novocaine containing one a-furfuryl group on the tertiary nitrogen. In our synthesis of secondary a-furfuryl(1) Zanetti and Bashour, THISJOURNAL, 61, 3133 (1939). (2) Zanetti and Beckmann, i b i d . , 50, 2081 (1928). (3) Von Braun and Kohler, Ber., 51, 86 (1918). (4) Von Braun and Braunsdorf, Bcr., 64, 2081 (1921).
amine^,^ tertiary amines were suspected in the small amount of high boiling residue accompanying each preparation. However, in the synthesis of these amines, unfavorable yields are obtained unless the purified secondary amines be made to react with furfuryl bromide. These tertiary amines are either high boiling liquids or solids and are miscible with most organic solvents. Their properties and the analyses are given in Table I. They are colorless when pure but turn yellow on standing. They have only faint ammoniacal odors. With hydrochloric acid in ether solution they form stable hydrochlorides. As in the case of the secondary furfurylamines, excess of hydrochloric acid must not be used as dark decomposition products will readily form.
Experimental Part In a flask provided with an air condenser the furfuryl bromide in ether solution is allowed to stand for one to three hours over crushed potassium hydroxide and then the secondary amine is added with agitation. With intermittent shak( 5 ) Zanetti and Bashour, TEISJOURNAL, 61, 3133 (1939).
